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首页> 外文期刊>BMC Medical Genomics >De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies
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De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies

机译：全球发育延迟，小头畸形和颅面畸形患者的ASXL3从头突变

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Background Currently, diagnosis of affected individuals with rare genetic disorders can be lengthy and costly, resulting in a diagnostic odyssey and in many patients a definitive molecular diagnosis is never achieved despite extensive clinical investigation. The recent advent and use of genomic medicine has resulted in a paradigm shift in the clinical molecular genetics of rare diseases and has provided insight into the causes of numerous rare genetic conditions. In particular, whole exome and genome sequencing of families has been particularly useful in discovering de novo germline mutations as the cause of both rare diseases and complex disorders. Case presentation We present a six year old, nonverbal African American female with microcephaly, autism, global developmental delay, and metopic craniosynostosis. Exome sequencing of the patient and her two parents revealed a heterozygous two base pair de novo deletion, c.1897_1898delCA, p.Gln633ValfsX13 in ASXL3 , predicted to result in a frameshift at codon 633 with substitution of a valine for a glutamine and introduction of a premature stop codon. Conclusions We provide additional evidence that, truncating and frameshifting mutations in the ASXL3 gene are the cause of a newly recognized disorder characterized by severe global developmental delay, short stature, microcephaly, and craniofacial anomalies. Furthermore, we expand the knowledge about disease causing mutations and the genotype-phenotype relationships in ASXL3 and provide evidence that rare, nonsynonymous, damaging mutations are not associated with developmental delay or microcephaly.
机译：背景技术目前，诊断患有罕见遗传疾病的个体可能是漫长而昂贵的，从而导致诊断性的征兆，并且尽管进行了广泛的临床研究，但在许多患者中仍未获得确定的分子诊断。基因组医学的最新出现和使用已导致罕见疾病的临床分子遗传学发生了范式转变，并提供了对众多罕见遗传病状成因的了解。特别是，家族的整个外显子组和基因组测序在发现从头种系突变作为罕见病和复杂疾病的起因方面特别有用。病例介绍我们介绍了一位六岁，非语言的非裔美国女性，患有小头畸形，自闭症，整体发育迟缓和原发性颅骨融合症。患者和她的两个父母的外显子组测序显示，ASXL3中的一个杂合的两个碱基从头缺失，即c.1897_1898delCA，p.Gln633ValfsX13，预计会导致第633位密码子移码，并用缬氨酸替代谷氨酰胺并引入提前终止密码子。结论我们提供了另外的证据，ASXL3基因的截短和移码突变是新近识别的疾病的原因，该疾病的特征是严重的整体发育延迟，身材矮小，小头畸形和颅面畸形。此外，我们扩展了有关引起疾病的突变以及ASXL3中基因型与表型关系的知识，并提供了证据表明罕见的，非同义的，破坏性突变与发育延迟或小头畸形无关。

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